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Ongoing Trials and the Future In Hormone Refractory Prostate Cancer. Cora N. Sternberg, MD, FACP Chairman, Department of Medical Oncology San Camillo and Forlanini Hospitals Rome, Italy. Novel Therapies and Targets for Prostate Cancer Can We Improve Upon the Results with Docetaxel ?.
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Ongoing Trials and the Future In Hormone Refractory Prostate Cancer Cora N. Sternberg, MD, FACP Chairman, Department of Medical OncologySan Camillo and Forlanini Hospitals Rome, Italy
NovelTherapiesandTargetsforProstateCancerCanWeImproveUpontheResultswithDocetaxel?NovelTherapiesandTargetsforProstateCancerCanWeImproveUpontheResultswithDocetaxel? • Angiogenesis inhibitors • Avastin • Thalidomide/Revlimid • Sunitinib • Antisense oligonucleotides • Genasense • Anti Clusterin OGX-011 • NovelChemoRx • Satraplatin • Epothilones • Abraxane Docetaxel Plus ? • Vaccines • GVAX • Provenge • Vitamin D Analogues • Calcitriol • EGFR inhibitors • Erlotinib, Gefitinib • 2C4 PDGF inhibitors • Imatinib Bone-targetedagents -Zometa -Denosumab -Atrasentan
NovelTherapiesandTargetsforProstateCancerCanWeImproveUpontheResultswithDocetaxel?NovelTherapiesandTargetsforProstateCancerCanWeImproveUpontheResultswithDocetaxel? • Apoptosis • Angiogenesis • Endothelin Receptor • Calcitriol • Vaccines
Can We Improve Upon the Results with Docetaxel ? Targeting Apoptosis
BCL-2 Expression In Prostate Cancer • Bcl-2 protein is a critical regulator of apoptosis in many tissues and is over expressed in the majority of HRPC • Bcl-2 plays a critical role in the transition from androgen-dependent to androgen-independent growth • Bcl-2 mediates resistance to androgen ablation and chemotherapy in HRPC
Changes in Gene Expression After Castration and During AI Progression Programmatic drift in gene expression upregulation of apoptosis- & progression-related genes Androgen Dependent Regressing Tumor Androgen Independent ++ PSA - Bcl-2 - EGFR - clusterin - IGFBP 2&5 - TGFb ++IGFBP 3 & 4 -YB-1 ++survivin - PSA ++ Bcl-2 ++Bclx-L - EGFR ++ clusterin ++++IGFBP 5 IGFBP 3 & 4 +c-myc +YB-1 -survivin ++ PSA +++ Bcl-2 ++Bclx-L + EGFR +++ clusterin ++ IGFBP 2 & 5 ++c-myc ++YB-1 ++ survivin Courtesy of Gleave M, modified
Antisense Oligonucleotide Activity TammI,LancetOncol2001;Jan;2(1):33-42
DocetaxelandOblimersenSodiumvsDocetaxelAloneinHRPCEORTC30021 RANDOMIZE Oblimersen7mg/kg/dayD1-7 Docetaxel75mg/m2D5q3w vs Docetaxel75mg/m2D1q3w Stratification: Institution, M0 vs M1 (measurable disease), prior estramustine, prior bisphosphonates 1st line Sternberg CN, Coordinator
Can We Improve Upon the Results with Docetaxel ? Targeting Angiogenesis
VEGF P P P P Survival Proliferation Migration ANGIOGENESIS VEGF: The Key Mediator of Angiogenesis, Endothelial Cell Growth and Vascular Permeability Environmentalfactors (Hypoxia,pH) Growthfactors (EGF,bFGF,PDGF, IGF-1,IL-1,IL-6) HIF-1α Genes involved in tumorigenesis (p53, p73, src, ras, vHL, Bcr-Abl) Upregulated VEGF binds and activates its receptor Docetaxel Stimulating signaling cascades Endothelial cell activation
CALGB 9040: Phase III study of Docetaxel+/- Bevacizumab in HRPC (n=1,020 pts) RANDOMIZE Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po daily Bevacizumab 15 mg/Kg Q3 wks Stratification Halabi nomogram Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg po daily Placebo CALGB, ECOG, NCIC Primary end point is PFS
NCI:RandomizedPhaseIITrialofDocetaxel+/-ThalidomideinHRPC RANDOMIZE Docetaxel30mg/m2QWx3Q4w+Thalidomide200mgorallydaily(n=50) vs Docetaxel30mg/m2QWx3Q4w(n=25) 2:1 Dahut WL, J Clin Oncol 2004 Jul 1;22(13):2532-9
NCI: Randomized phase II Trial of Docetaxel +/- Thalidomide in HRPC 28.9 mos 14.7mos At 18 mos, OS 68.2% vs 42.9% alive (p=.11) Dahut WL, J Clin Oncol. 2004 Jul 1;22(13):2532-9
Can We Improve Upon the Results With Docetaxel ? TargetingtheEndothelinReceptor
Inhibition of apoptosis Induce proliferation
Atrasentan: A Selective Endothelin-A Receptor Antagonist • Orallybioavailable • Oncedailydosing • 1800xmoreselectiveforETAthanETB OpgenorthTJ,etal.JPharmacolExpTher.1996Feb;276(2):473-81. CarducciMA,etal.JClinOncol.2002Apr15;20(8):2171-80. NelsonJB,CarducciMA.BJUInt.2000Apr;85Suppl2:45-8. Nelson,ProstateJ1999;1:126.
Characteristics Orally bioavailable Daily dosing t ½ = 25 hours 2 large randomized trials in HRPC Meta-analysis of these trials -10 mg dose at ASCO 2005 Meta-analysis ↓ in bone pain and time to bone pain ↓ risk of disease progression ↓ in rise of biomarkers Delay in time to biochemical progression ↑disease specific QoL Atrasentan A potent, Selective ETA Receptor Antagonist Vogelzang N, ASCO 2005
Phase III Study of Docetaxel + Placebo vs Docetaxel + Atrasentan in HRPC (SWOG 0421) • Eligibility: • Progressive mets HRPC • ECOG PS <2, selected 3 • Bone mets • Stratification: • Type of prog • Pain • Extra-skeletal disease • Bisphoshonates RANDOMIZE Docetaxel 75 mg/m2 Q3 wks Prednisone 10mg + Atrasentan 10 mg Docetaxel 75 mg/m2 Q3 wks Prednisone 10 mg + Placebo Primary endpoint is PFS
Can We Improve Upon the Results with Docetaxel ? CalcitriolIsthePrincipalActiveMetaboliteofVitaminD
ASCENT Study: Randomized study of Docetaxel +/-high-dose Calcitriol in HRPC (n=250 pts) Stratification Pain level PPI ≥ 2 or AS ≥ 10 vs. PPI < 2 or AS < 10 Karnofsky ≤ 70 vs. ≥ 80 RANDOMIZE Docetaxel 36 mg/m2 weekly 3 of 4 wks + DN-101 45 mg po daily Docetaxel 36 mg/m2 weekly 3 of 4 wks + Placebo Primary end point: PSA response ASCENT : Androgen-independent prostate cancer Study of Calcitriol Enhancing Taxotere
ASCENT Study: Survival 7.1 mos improved median survival 1.00 DN-101 Placebo 0.75 23.5 mos Median Survival DN-101 23.5 mos (estimated) Placebo 16.4 mos (observed) Probability of Survival 16.4 mos 0.50 0.25 Hazard Ratio (95% CI) Unadjusted 0.70 (0.48 – 1.028), P = 0.070 Multivariate 0.67 (0.45 – 0.97), P = 0.035 0.00 0 12 24 36 48 60 72 84 Weeks Beer T, ASCO 2005
ASCENT II Study: Phase III study of Docetaxel +/-high-dose Calcitriol in HRPC (n=900) RANDOMIZE Docetaxel 36 mg/m2 d2, weekly 3 of 4 wks + DN-101 45 µgpo daily Docetaxel 75 mg/m2 every 3 weeks + prednisone Primary end point: Overall Survival Secondary Endpoints: SRE rate, TE rate, GI rate, Overall safety
Can We Improve Upon the Results with Docetaxel ? Vaccine Therapy
Rationale for Treating Asymptomatic HRPC Patients • Reluctance to start chemotherapy if asymptomatic • Randomized trials showing survival benefit do not define when chemotherapy should be initiated • Treatment options are limited
APC8015(Provenge)VaccineTherapywithPulsedDendriticCells Dendritic-cell precursors are harvested by leukapheresis APC: Antigen presenting cells MHC Pulse with PAP-GM-CSF fusion protein for 40 hrs Purified Dendritic Cells with prostate-specific peptides Inject Back Into Prostate Cancer Patient Prostate Cancer Patient Phase I/II results published show safety and a clear dose-related biologic activity Small E, JCO, 2000
APC Asymptomatic Metastatic HRPC Treatment Schema 9901 n = 127 P R O G R E S S I O N R A N D O M I Z E APC-Placebo Q 2wks x 3 n=45 APC8015F Q 2 wks x 3 APC 8015 Q 2 wks x 3 n=82 Long-Term Follow-up 2:1 TTP primary endpoint. TDRP secondary endpoint Small E, ASCO, 2005
Overall Survival9901 - Intent to Treat 4.5 mos difference in median survival! 100 APC8015 (n=82) Placebo (n=45) 75 25.9 mos P = 0.01 (log-rank) HR = 1.7 (95% CI: 1.126, 2.563) 50 21.4 mos Percent Survival 34% alive 36 mos 25 11% alive 36 mos 0 0 10 20 30 40 Survival (months) Small E, ASCO 2005 Phase 3 Trial #D9901
Meta-analysis of Trials 9901 and 9902A Overall Survival Identical inclusion criteria, Rx, design, endpoints 100 APC8015 (n=147) APC-Placebo (n=78) 23.2 mos 75 P = 0.011 (log rank) HR = 1.50 [95% CI: 1.10, 2.05] 50 18.9 mos Percent Survival (Each vertical line representsa censored value.) 25 combined analysis of 2 studies shows a significant survival advantage 0 0 10 20 30 40 Survival (months) 4.3 mos difference in median survival! Higano C, abst PS1, ECCO 13, 2005
Provenge Dendritic Cell Vaccine • Acid phosphatase - not expressed by all PC cells • Immunologic data are lacking in most patients • Studies are small and not designed for survival (huge alpha error)
GVAX Prostate Cancer Vaccine • Cellularvaccinecomprisedof2allogeneiccelllines,LNCaP(lymphnodemetastasis)andPC-3(bonemetastasis) • ThecelllinesaremodifiedtosecreteGM-CSFandthenlethallyirradiatedtopreventfurthercelldivision • GVAXvaccinedemonstratesimmunogenicityandclinicalactivityinmetastaticHRPCptswhichappearstobedose-dependent(phaseIItrials) Small E, ASCO 2004, abst # 4565
Prostate GVAXPhase III Studies survival GVAX VITAL-1 HRPC w/ mets Chemo-naive asymptomatic Docetaxel + Pred N = 600 survival Docetaxel + GVAX VITAL-2 HRPC w/ mets Taxane-naive symptomatic Docetaxel + Pred N = 600
Immunotherapy for HRPC • It is well placed for asymptomatic patients • Treatment is not toxic • Treatment is costly in view of the technology used • A promising approach which cannot yet be recommended
Satraplatin Chemical Structure bis-(acetato)-ammine dichloro- (cyclohexylamine) platinum IV Satraplatin is a 3rd generation oral platinum compound that has demonstrated in vitro activity against taxane - resistant cell lines
Satraplatin and Prednisone vs Prednisone in Chemotherapy Naïve HRPC (n=380) Satraplatin 100 mg/m² d1-5 q 35 days (for a max of 10 cycles) + Prednisone 10 mg twice daily until progression or intolerable toxicity R A N D O M I Z E HRPC And no prior chemotherapy Prednisone 10 mg twice daily until progression or intolerable toxicity 1:1 1° Endpoint: Overall survival and time to pain progression 2° Endpoints: PPI, PSA response, TTP, QoL, safety EORTC 30972
Progression-free Survival 100 Median: Pred: 2.5 months (95% CI: 2.1 – 4.7) Pred + Satraplatin 5.2 months (95% CI: 2.8 – 13.7) HR: 0.50 (95% CI: 0.28 – 0.92) 90 80 70 60 5.2 mos 50 40 p=0.023 30 20 2.5 mos 10 0 (months) 0 3 6 9 12 15 18 21 24 27 O N Number of patients at risk : 23 23 10 5 3 3 1 1 0 0 Pred 25 27 18 11 11 11 6 5 5 3 Pred+ Satraplatin Sternberg CN, Oncol 2005; 68:2-9
The SPARC Study in 2003 International double-blind randomized Phase III study of Satraplatin Plus Prednisone vs Placebo Plus Prednisone in patients with HRPC previously treated with one cytotoxic chemotherapy regimen Principal Investigators Cora Sternberg, Daniel Petrylak, Oliver Sartor, Fred Witjes Clinical Protocol No. GPC SAT3-03-01
Satraplatin and Prednisone Against Refractory Cancer SPARC Trial (n=950) Metastatic HRPC after 1 prior chemo Stratify ECOGPS 0-1 vs 2 PPI 0-1 vs 2-5 PSA vs disease prog R A N D O M I Z E Satraplatin 80 mg/m2 po daily d 1-5 q35 days + Prednisone 5 mg po BID continuously Placebo po daily days 1-5 + Prednisone 5 mg po BID continuously 2:1 1° Endpoint: 30% increase in TTP with 85% power (p=.034) 2° Endpoints: OS 12 mos to 15.6 mos & time to pain progression
Satraplatin and Prednisone Against Refractory Cancer • This is the first registration trial in 2° line HRPC • There are no drugs approved in this setting • It represents a major area of unmet medical need • A total of 950 patients were accrued in more than 200 centers in 15 countries on 4 continents • This is, therefore, one of the largest registration trials in oncology and one of few that are double blind
Hormone Refractory Prostate Cancer Conclusions • DocetaxelandPrednisoneimprovessurvivalandisareferenceforsubsequenttrials(incombinationwithtargetedagents,hormonenaïve,secondline,andintheadjuvantandneo-adjuvantsetting) • 2ndlinetherapyofHRPCisanunmetmedicalneed • SatraplatinisextremelypromisingandfinalsurvivalresultsoftheSPARCtrialareanxiouslyawaited